The present invention relates to a process for continuously preparing chromanol ester derivatives, in particular for continuously preparing carboxylic esters of tocopherols and tocotrienols by continuous acylation with carboxylic acids or carboxylic anhydrides.
Compounds having vitamin E activity, such as the naturally occurring chromanol derivatives of the tocopherol and tocotrienol group, are important fat-soluble antioxidants. A vitamin E deficiency in humans and animals leads to pathophysiological conditions. Vitamin E compounds therefore have a high economic value as additives in the food and feed sectors, in pharmaceutical formulations and in cosmetics applications. The compounds having vitamin E activity, in particular xcex1-tocopherol, are used for this principally in the form of their acetate esters. An economic process for preparing chromanol ester derivatives is therefore of high importance.
It is known to react tocopherol derivatives batchwise with acetic anhydride to give the corresponding acetate esters.
EP 850 937 describes in the examples a batchwise process for preparing xcex1-tocopherol acetate by heating under reflux xcex1-tocopherol with acetic anhydride in a stirred flask having an attached reflux condenser. The reaction discharge is then worked up by distillation.
DE 19 603 142 describes a process for preparing d1-xcex1-tocopherol acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol (IP) in a solvent at elevated temperature and subsequent acetylation of the resultant tocopherol. The tocopherol is acetylated by acid-catalyzed reaction with excess acetic anhydride. The reaction discharge is worked up by fractional distillation under reduced pressure. For the continuous reaction of 2,3,5-trimethylhydroquinone with phytol, a reaction column is proposed into which a mixture of cyclic carbonate, the catalyst, TMH and IP are fed in laterally. The hydrocarbon and the water formed are removed at the top of the column and hot cyclic carbonate and vitamin E are taken off from the bottom. No description is given of the process design of the subsequent acylation. An example mentions that the tocopherol isolated after phase separation was esterified with acetic anhydride.
A process for preparing d1-xcex1-tocopherol or d1-xcex1-tocopherol acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol (IP) in the presence of a mixture of orthoboric acid and certain aliphatic di- or tricarboxylic acids with or without subsequent esterification with acetic anhydride is described in DE 42 08 477. According to DE 42 08 477, the tocopherol prepared is converted in a similar manner to DE 19 603 142 into tocopherol acetate batchwise with excess acetic anhydride under acid catalysis and purified by fractional distillation under a greatly reduced pressure. The initial molar ratio of acetic anhydride/tocopherol was greater than 1.3 mol/mol and the acid concentration was approximately 0.055 mol % based on tocopherol.
EP 0 784 042 claimed hydrogen bis(oxalato)borate as protic acid catalyst for the Friedel-Crafts condensation of trimethylhydroquinone with isophytol and the acylation of phenols, for example tocopherol. In an example the acylation of tocopherol is described. For this, tocopherol was charged into a flask together with acetic anhydride and hydrogen bis(oxalato)borate and the reaction mixture was heated to reflux for one hour under an argon atmosphere. The initial molar ratio of acetic anhydride/tocopherol was greater than 1.1 mol/mol and the borate concentration was approximately 0.5 mol %, based on tocopherol. After concentration on a rotary evaporator, tocopherol acetate was obtained in a purity of 87% at a yield of 92%. This batch process has the disadvantage that both yield and purity are still not satisfactorily high. In addition, carrying out the reaction in an argon atmosphere is associated with high costs for industrial production.
JP 49 055 633 describes the batchwise preparation of tocopherol acetate by acylation of tocopherol with acetic anhydride in the presence of inorganic solid acids which are insoluble in the reaction mixture. In the process, tocopherol and acetic anhydride in the solvent toluene are heated in the presence of the catalyst for about 4 hours under reflux, a product purity of about 91% being achieved. As an example of the catalyst, SiO2/Al2O3 is mentioned. Disadvantages of the process are the low space-time yields and the low product purities.
The acylation of tocopherol with acetic anhydride in the presence of a mixture of hydrochloric acid and zinc or zinc chloride is described in JP 56 073 081. According to this process, tocopherol is heated with acetic anhydride and the catalyst mixture at from 10 to 30xc2x0 C. for from 0.5 to 2 hours. The catalyst is then removed and the reaction mixture is washed with water. Hydrochloric acid is used at a concentration of from 0.02 to 0.06 mol % based on tocopherol, the zinc is used at a concentration of from 0.01 to 0.2 mol % based on tocopherol and the zinc chloride is used at a concentration of from 0.001 to 0.1 mol % based on tocopherol. Acetic anhydride is used at a from 1.2 to 1.5 times molar excess. The process gives tocopherol acetate at a yield of 92.5% based on tocopherol. The complex workup, the batchwise reaction procedure and the solids handling cause a low space-time yield in this process, despite the short reaction time.
DE 2 208 795 describes the reaction of trimethylhydroquinone with isophytol in the presence of a mixture of a Lewis acid and a protic acid in an inert solvent. The catalyst system which can be used is, for example, a mixture of zinc chloride with NaHSO4, H2SO4 or p-toluenesulfonic acid. Optionally, the reaction discharge can be reacted with acetic anhydride without further workup. For this acetic anhydride is added to the reaction mixture and heated under reflux for about 6 hours. A disadvantage of this process is the low space-time yield for the acylation.
A continuous process for reacting trimethylhydroquinone with isophytol, phytol or phytadienes in the presence of acid condensation catalysts in a packed column is described in U.S. Pat. No. 3,444,213. In this process the reactants, optionally premixed or dissolved in an inert solvent, are applied to the top of a heated column and the resultant reaction water is evaporated via the top of the column. The column, however, is only a heated tubular reactor without evaporator, and not a reactive distillation column. The product arising at the bottom of the column is reacted in the course of one hour batchwise with acetic anhydride in the solvent pyridine. A disadvantage of this process is the low space-time yield of the acylation and the use of a solvent.
A further continuous process for reacting trimethylhydroquinone with isophytol is described in CS 205 951. In this patent also, the acylation is performed batchwise using acetic anhydride.
All known processes of the prior art for acetylating tocopherol derivatives have the disadvantage of high residence times and thus low space-time yields and high capital costs. In all cases the tocopherol derivative, in the absence or presence of a catalyst, is reacted batchwise with acetic anhydride and the reaction mixture is worked up by distillation. In this case, firstly the acetic acid and the acetic anhydride are removed at low vacuum and the acetate of the tocopherol derivative is then purified by distillation under a high vacuum.
Furthermore, the yields of these processes, at about from 92 to 95%, are insufficiently satisfactory. The acetic anhydride is always used in a relatively high excess of at least 1.2 mol per mole of tocopherol derivative, in order to achieve a sufficient conversion rate at an acceptable reaction time. As implied by EP 0 784 042, reduction in the excess of acetic anhydride is only possible if the acid concentration is considerably increased. However, this leads to an increased formation of byproducts and thus to decreased yields and product purity.
It is an object of the present invention, therefore, to provide a further process for preparing chromanol ester derivatives having advantageous properties, which process no longer exhibits the disadvantages of the prior art and which gives chromanol ester derivatives in high yields and high space-time yields.
We have found that this object is achieved by a process for continuously preparing chromanol ester derivatives of the formula I, 
where
R1, R2, R3, R4, R5, R6, R7 and R8 independently of one another are hydrogen or an unsubstituted or substituted, branched or unbranched C1-C10-alkyl radical and
the dashed bonds are a possible additional Cxe2x80x94C bond,
by reacting continuously fed chromanol derivatives of the formula II 
with continuously fed acylating agent selected from the group consisting of carboxylic acids of the formula IIIa
R8-COOHxe2x80x83xe2x80x83IIIa
and carboxylic anhydrides of the formula IIIb, 
where
R9 is hydrogen or an unsubstituted or substituted, branched or unbranched C1-C10-alkyl radical,
in a reactor
and continuously removing the reaction products from the reactor.
An unsubstituted or substituted, branched or unbranched C1-C10-alkyl radical is, for the radicals R1, R2, R3, R4, R5, R6, R7, R8 and R9 independently of one another, for example, unsubstituted or substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl or decyl, preferably unsubstituted or substituted C1-C4-alkyl, for example methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl.
The type of substituents is not critical. The C1-C10-alkyl radicals, depending on free bonds available, can contain up to 6 substituents, preferably selected from the group consisting of xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94CN, xe2x80x94COOH, or halogen, in particular F or Cl.
In a preferred embodiment the branched or unbranched C1-C10-alkyl radicals of the radicals R1, R2, R3, R4, R5, R6, R7, R8 and R9 are not substituted.
Particularly preferred radicals for R4, R5, R6 and R7 are independently of one another hydrogen or methyl, in particular methyl.
Particularly preferred radicals for R1, R2 and R3 are independently of one another hydrogen or methyl.
Particularly preferred radicals for R8 are methyl or ethyl, in particular methyl.
Particularly preferred radicals for R9 are ethyl or methyl.
In a preferred embodiment of the inventive process, the chromanol derivatives of the formula II are tocopherol derivatives and tocotrienol derivatives having vitamin E activity, in particular the naturally occurring tocopherols and tocotrienols.
For the preferred naturally occurring tocopherols and tocotrienols, in formula II the radicals R4 to R7 are methyl. The group of tocopherols (IIa-d) has a saturated side chain, and the group of the tocotrienols (IIe-h) have an unsaturated side chain: 
Particularly preferably, in the inventive process xcex1-tocopherol of the formula IIa is used as chromanol derivative of the formula II.
The chromanol derivatives of the formula II used in the inventive process, in particular the preferred tocopherols and tocotrienols of the formulae IIa to IIh can be used as individual compounds which can be present in any desired purity. Generally, the purity of individual tocopherols and tocotrienols is from 90% to 97%, but purer compounds and less pure crude products can also be used. The compounds can also be used as a mixture of different chromanol derivatives of the formula II and the inventive process correspondingly leads to a mixture of chromanol ester derivatives of the formula I. This can be the case, for example, when tocopherols or tocotrienols are used from natural sources without further separation of the individual tocopherols and tocotrienols. The chromanol derivatives of the formula II can be enantiomerically pure, a racemic mixture, or a diastereomer mixture.
The chromanol derivatives of the formula II can be chemically prepared or isolated from natural sources, for example the evaporator condensates produced in vegetable oil deodorization and purified, as described in Ullmann""s Encyclopedia of Industrial Chemistry, Vol. A 27 (1996), VCH Verlagsgesellschaft, Chapter 4., 478-488, Vitamin E.
The carboxylic acids of the formula IIIa or carboxylic anhydrides of the formula IIIb used as acylating agents in the inventive process can be used as individual substances or as mixtures.
In a preferred embodiment, the acylating agents used are the carboxylic anhydrides of the formula IIIb.
The carboxylic anhydrides of the formula IIlb can be used as pure carboxylic anhydrides or as mixed carboxylic anhydrides. In a preferred embodiment, pure carboxylic anhydrides are used, so that R8=R9. Particular preference is given to the acetylation using acetic anhydride as carboxylic anhydride of the formula IIIb where R8=R9=methyl.
In the inventive process the reactants, the chromanol derivatives of the formula II and the acylating agents, selected from the group consisting of carboxylic acids of the formula IIIa and carboxylic anhydrides of the formula IIIb, are fed continuously to a reactor, reacted in the reactor and then the reaction products are continuously removed from the reactor.
In the case of reactions having a high initial rate, it can be advantageous to connect upstream of the reactor a further preliminary reactor in which a partial conversion already takes place. It can also be advantageous to mix the reactants before feeding into the reactor, so that here also a partial conversion takes place.
The term xe2x80x9creacted in a reactorxe2x80x9d therefore means that in this reactor conversion of the reactants still takes place. This conversion in the reactor can, for example when a preliminary reactor is connected upstream, be at least 1%, preferably at least 20%, particularly preferably at least 50%, very particularly preferably at least 80%, of the conversion rate which is achievable overall. In a preferred embodiment, the total achievable conversion occurs in the reactor.
When the reactants are fed and reacted, in addition solvents can be used. Particularly advantageously, however, the process may be carried out without addition of solvents.
The inventive process may be particularly advantageously carried out by continuously removing at least one reaction product from the reaction mixture during the reaction in the reactor, that is to say simultaneously with the reaction. Accordingly, the water formed from the acylating agent (when carboxylic acids of the formula IIIa are used as acylating agent) or the resultant carboxylic aci R9-COOH (when carboxylic anhydrides of the formula IIIb are used as acylating agent) or the resultant chromanol ester derivatives of the formula I or both are removed from the reaction mixture during the reaction.
In a preferred embodiment, only water or the carboxylic acid R9-COOH is removed from the reaction mixture. This removal is also preferably performed continuously.
There are many reactor designs which come into consideration for the preferred inventive process. Preferred reactors should have the property of enabling continuous reaction with simultaneous removal of at least one reaction product. For example, reactors which can be used are stills having an attached column, divided wall columns, extraction columns, membrane reactors or reaction columns.
In a particularly preferred embodiment of the inventive process, the reaction is performed in a reaction column as reactor.
As described above, it can be advantageous to connect upstream of this reaction column a reactor (preliminary reactor) in which a portion of the conversion already takes place. In a particularly preferred embodiment, the reaction is performed in a reactor, in particular in a reaction column.
A reaction column, which can be designed in very different ways, has the property as a reactor of enabling simultaneously a reaction of reactants and the thermal removal of at least one reaction product.
Preferably the reaction column consists of a bottom and a superstructure which enables rectification, for example a fractionation column.
In this preferred embodiment, using a reaction column it is further advantageous to set the reaction parameters in such a manner that
A the chromanol derivatives of the formula II react with the acylating agent on the internals and possibly in the bottom phase of the reaction column,
B the H2O formed in the reaction with the acylating agent (use of carboxylic acids of the formula IIIa as acylating agent) or the carboxylic acid R9-COOH formed (use of carboxylic anhydrides of the formula IIIb as acylating agent) is continuously removed with the overhead stream of the reaction column and
C the chromanol ester derivatives of the formula I formed in the reaction are continuously removed with the bottom stream of the reaction column.
Depending on the type of design of the reaction column and the reactants used, this is achieved by varying reaction parameter settings. Suitable reaction parameters are, for example, temperature, pressure, reflux ratio in the column, design of the column, heat transfer and residence time, in particular in the bottom phase, energy input or the molar ratio of the reactants, which can be optimized by those skilled in the art by routine experiments so that the features A, B and C are achieved.
Typically, in the inventive process, the pressure at the column top is set so that the temperature in the bottom is from 100 to 300xc2x0 C. preferably from 130 to 180xc2x0 C.
The residence time in the reaction column is typically from 15 minutes to 6 hours, preferably from 30 minutes to 3 hours.
The initial ratio of the reactants is not critical, the molar ratio of acylating agent, that is to say the carboxylic acids of the formula IIIa or the carboxylic anhydrides of the formula IIIb to the chromanol derivative of the formula II is usually from 1.0 to 5.0, preferably from 1.0 to 1.3.
The inventive process may be carried out particularly advantageously if the reaction is carried out in the presence of a catalyst.
A catalyst is a substance which is able to accelerate the acylation of chromanol derivatives of the formula II.
Preferred catalysts are acid or basic acylation catalysts, for example, sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, acetates, zinc chloride, triethylamine, pyridine, tertiary bases, hydrogen bis(oxalato)borate, acid or basic ion exchangers, zeolites, SiO2/Al2O3 or inorganic solid acids.
Particularly preferred catalysts are homogeneous basic or acid catalysts, in particular sulfuric acid or phosphoric acid, and heterogeneous catalysts, in particular acid ion exchangers or acid zeolites, which are introduced in a targeted manner into the reaction zone.
The homogeneous catalysts have the advantage that they can be pumped in the liquid state into the fractionation column. The heterogeneous catalysts have the advantage that they do not lead to contamination of the product or to impairment of the color index of the product during workup.
The homogeneous catalysts are preferably used in dilute form. Thus, for example, sulfuric acid and phosphoric acid are typically used at a concentration from 0.01 to 50%, preferably at a concentration from 0.1 to 1.0%. The amount of the homogeneous catalysts is preferably dimensioned such that their concentration is from 0.001 to 1.0 mol %, based on the chromanol derivative of the formula II, preferably from 0.01 to 0.1 mol %, based on the chromanol derivative of the formula II.
The heterogenous catalysts are preferably integrated into the fractionation column internals.
In a particularly preferred embodiment of the inventive process, the reaction column internals used are column trays below the highest feed point for the reactants, and are structured packings above the highest feed point for the reactants. Particularly advantageous column trays make high residence time of the liquid possible, with the residence time on the reaction column internals preferably being at least 30 min.
Preferred column trays are, for example, valve trays, preferably bubble-cap trays, or related types, for example tunnel trays or Thormann trays.
Preferred structured packings are, for example, structured packings of the following types: Melapack(R) (Sulzer), BX(R) (Sulzer), B1(R) (Montz) or A3(R) (Montz) or packings of comparable designs.
In a further particularly preferred embodiment of the inventive process, the higher-boiling reactant, if appropriate together with the homogeneous catalyst, is fed into the reaction column above the lower-boiling reactant.
Particularly advantageously, the process may be carried out by the heat being fed into the reaction column, in addition to an evaporator, via heat exchangers mounted externally to the reaction column, or via heat exchangers situated directly on the column trays.
In addition, the introduction of a stripping gas, preferably nitrogen or carbon dioxide, into the reaction column is advantageous.
This facilitates the removal of water or the resultant carboxylic acid R9-COOH.
In addition, the inventive process may be carried out advantageously by removing excess acylating agent, that is to say the carboxylic acid of the formula IIIa or the carboxylic anhydride of the formula IIIb, from the effluent bottom stream in a downstream evaporator, and recirculating it to the column with or without ejection of a substream. As a result, high yields are achieved based on the acylating agent (carboxylic acid of the formula IIIa or carboxylic anhydride of the formula IIIb).